The effect of genetic background on behavioral manifestation of Grid2 mutation

Cendelín, Jan; Tůma, Jan; Korelusová, I; Vožeh, F

doi:10.1016/j.bbr.2014.06.023

Cited by 21 publications

(14 citation statements)

References 55 publications

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“…The lack of cerebellar degeneration in the young SCA1 mice, our correlational analysis and the fact that the mice with cerebellar-specific degeneration exhibit a number of opposite abnormalities (lack of immobility in the FST and MWM, reduced thigmotaxis in the OF and higher relative times in the open arms in the EPM) [51][52][53][54][55] suggest that the behavior of the SCA1 mice may be relatively independent of motor deficits and cerebellar degeneration. On the other hand, the SCA1 mice suffer from cerebellar inflammation prior to the onset of cerebellar degeneration 33 , and cerebellar inflammation is able to induce depressive-like behavior in mice 56 .…”

Section: Discussionmentioning

confidence: 82%

Hippocampal mitochondrial dysfunction and psychiatric-relevant behavioral deficits in spinocerebellar ataxia 1 mouse model

Tichánek

Šalomová

Jedlička

et al. 2020

Sci Rep

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Spinocerebellar ataxia 1 (SCA1) is a devastating neurodegenerative disease associated with cerebellar degeneration and motor deficits. However, many patients also exhibit neuropsychiatric impairments such as depression and apathy; nevertheless, the existence of a causal link between the psychiatric symptoms and SCA1 neuropathology remains controversial. This study aimed to explore behavioral deficits in a knock-in mouse SCA1 (SCA1 154Q/2Q) model and to identify the underlying neuropathology. We found that the SCA1 mice exhibit previously undescribed behavioral impairments such as increased anxiety-and depressive-like behavior and reduced prepulse inhibition and cognitive flexibility. Surprisingly, non-motor deficits characterize the early SCA1 stage in mice better than does ataxia. Moreover, the SCA1 mice exhibit significant hippocampal atrophy with decreased plasticity-related markers and markedly impaired neurogenesis. Interestingly, the hippocampal atrophy commences earlier than the cerebellar degeneration and directly reflects the individual severity of some of the behavioral deficits. Finally, mitochondrial respirometry suggests profound mitochondrial dysfunction in the hippocampus, but not in the cerebellum of the young SCA1 mice. These findings imply the essential role of hippocampal impairments, associated with profound mitochondrial dysfunction, in SCA1 behavioral deficits. Moreover, they underline the view of SCA1 as a complex neurodegenerative disease and suggest new avenues in the search for novel SCA1 therapies. Spinocerebellar ataxia type 1 (SCA1) is a lethal dominantly-inherited neurodegenerative disease, caused by CAG repeat expansion (> 40 CAG repeats) in the ataxin-1 encoding gene (ATXN1) 1. This mutation results in ataxin-1 protein toxicity and aggregation which leads, in particular, to cerebellar and brainstem degeneration 2 , although ATXN1 is widely expressed throughout the brain 1. SCA1 symptoms usually appear in early middle-age and include motor incoordination and gait deficits followed by muscular and swallowing problems in the later stages of the disease 3. However, in a similar way to other types of spinocerebellar ataxias (SCAs), over 50% of patients also demonstrate neuropsychiatric issues 4-7 including cognitive impairments, anxiety, apathy and depression 7-9. Interestingly, in contrast to progressive ataxia, the psychiatric impairments tend to remain relatively stable over time 8. Although they are often overlooked, they profoundly impact the quality of life and health outcomes of patients with SCA1 and related diseases 9. However, the question of whether these psychiatric impairments are causally linked to SCA1 neuropathology, or if they represent an emotional response to SCA1 diagnosis and subsequent physical disability, remains controversial 9 .

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Section: Discussionmentioning

confidence: 82%

Hippocampal mitochondrial dysfunction and psychiatric-relevant behavioral deficits in spinocerebellar ataxia 1 mouse model

Tichánek

Šalomová

Jedlička

et al. 2020

Sci Rep

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“…34,35 Of note, in family AAD001, heterozygous carrier women showed even milder ataxic symptoms and had normal intellectual development, without overt symptoms at ages 51, 43, and 32 years, respectively, for patients 17, 21, 41 (figure 1). 34,35 Of note, in family AAD001, heterozygous carrier women showed even milder ataxic symptoms and had normal intellectual development, without overt symptoms at ages 51, 43, and 32 years, respectively, for patients 17, 21, 41 (figure 1).…”

Section: Individualsmentioning

confidence: 99%

GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia

et al. 2015

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In humans, GRID2 had only been involved in ataxia through complete loss-of-function mutations due to exon deletions. We report the first point mutations in this gene, with putative gain-of-function mechanisms, and a semidominant transmission as was observed in the Lurcher mice model. Of note, cerebellar ataxia is the core phenotype, but with variable severity ranging from very mild adult-onset to congenital-onset ataxias linked to both the heterozygous and homozygous state of the variant, and the position of the mutation.

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“…Moreover, the mutations appear in different mouse strains and these mutants retain specific phenotypic traits of the original strains. The importance of the genetic background for behavioral manifestation has been shown in gain-of-function (Cendelin et al, 2014 ) as well as loss-of-function mutations (Lalouette et al, 2001 ). Furthermore, the review by D'hooge and de Deyn ( 2001 ) showed that sex differences, age, nutrition, stress, infections as well as experimental protocol, apparatus, and data analysis could markedly influence results in the Morris water maze task (Morris, 1984 ).…”

Section: Introductionmentioning

confidence: 99%

“…Lurcher mutation exists in two phenotypically undistinguishable alleles, the original one, Grid2 Lc (Zuo et al, 1997 ), and Grid2 Lc−J (de Jager et al, 1997 ). For experiments, Grid2 Lc mutants have been used, e.g., in B6CBA and C3H (Caddy and Biscoe, 1979 ; Cendelin et al, 2014 ) strain backgrounds.…”

Section: Introductionmentioning

confidence: 99%

Mutation-related differences in exploratory, spatial, and depressive-like behavior in pcd and Lurcher cerebellar mutant mice

Tůma

Kolinko

Vožeh

et al. 2015

Front. Behav. Neurosci.

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The cerebellum is not only essential for motor coordination but is also involved in cognitive and affective processes. These functions of the cerebellum and mechanisms of their disorders in cerebellar injury are not completely understood. There is a wide spectrum of cerebellar mutant mice which are used as models of hereditary cerebellar degenerations. Nevertheless, they differ in pathogenesis of manifestation of the particular mutation and also in the strain background. The aim of this work was to compare spatial navigation, learning, and memory in pcd and Lurcher mice, two of the most frequently used cerebellar mutants. The mice were tested in the open field for exploration behavior, in the Morris water maze with visible as well as reversal hidden platform tasks and in the forced swimming test for motivation assessment. Lurcher mice showed different space exploration activity in the open field and a lower tendency to depressive-like behavior in the forced swimming test compared with pcd mice. Severe deficit of spatial navigation was shown in both cerebellar mutants. However, the overall performance of Lurcher mice was better than that of pcd mutants. Lurcher mice showed the ability of visual guidance despite difficulties with the direct swim toward a goal. In the probe trial test, Lurcher mice preferred the visible platform rather than the more recent localization of the hidden goal.

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The effect of genetic background on behavioral manifestation of Grid2 mutation

Cited by 21 publications

References 55 publications

Hippocampal mitochondrial dysfunction and psychiatric-relevant behavioral deficits in spinocerebellar ataxia 1 mouse model

Hippocampal mitochondrial dysfunction and psychiatric-relevant behavioral deficits in spinocerebellar ataxia 1 mouse model

GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia

Mutation-related differences in exploratory, spatial, and depressive-like behavior in pcd and Lurcher cerebellar mutant mice

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